The invention relates to insecticidal mixtures of fipronil and agonists or antagonists of nicotinic acetylcholine receptors for the protection of industrial materials and plants.

The invention relates to synergistic insecticidal mixtures of fipronil and agonists or antagonists of nicotinic acetylcholine receptors for the protection of industrial materials and as crop protection agents.
It is already known that fipronil can be employed for controlling wood-damaging animals (EP-295 117; U.S. Pat. No. 5,232,940). The very low vapour pressure of these compounds is an advantage.
However, relatively high concentrations are required when fipronil is used on its own. It is very difficult to deliver the concentrations required for activity sufficiently deep into the wood to be protected.
Furthermore, it is also known that agonists and antagonists of nicotinic acetylcholine receptors can be used for controlling insects and wood-damaging animals. Here, the active compound also has to be employed in relatively high concentrations to achieve an acute effect in the lower layers of the wood. In many instances, sub-lethal doses result in a change of the behaviour of the species, but in many cases these are reversible.
It has now been found that mixtures of fipronil and at least one agonist or antagonist of acetylcholine receptors of the formula (I) have synergistic activity and are suitable for protecting industrial materials, in particular wood, against attack by insects. These mixtures are also suitable in crop protection for controlling animal pests. Owing to this synergism, significantly lower amounts of active compounds can be used, i.e. the activity of the mixture is greater than the activity of the individual components.
The agonists and antagonists of the nicotinic acetylcholine receptors are known compounds, which are known from the following publications:
European Published Specifications Nos 464 830, 428 941, 425 978, 386 565, 383 091, 375 907, 364 844, 315 826, 259 738, 254 859, 235 725, 212 600, 192 060, 163 855, 154 178, 136 686, 303 570, 302 833, 306 696, 189 972, 455 000, 135 956, 471 372, 302 389;
German Offenlegungsschriften (German Published Specifications) Nos 3 639 877, 3 712 307;
Japanese Published Specifications Nos 03 220 176, 02 207 083, 63 307 857, 63 287 764, 03 246 283, 04 9371, 03 279 359, 03 255 072;
U.S. Pat. Nos. 5,034,524, 4,948,798, 4,918,086, 5,039,686, 5,034,404;
PCT Applications Nos WO 91/17 659, 91/4965;
French Application No. 2 611 114;
Brazilian Application No. 88 03 621.
The generic formulae and definitions described in these publications and the individual compounds described therein are expressly incorporated herein by reference.
Some of these compounds are summarized under the term nitromethylenes and related compounds.
Preferably, these compounds can be summarized under the general formula (I)
in which
R represents hydrogen, optionally substituted radicals acyl, alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;
A represents a monofunctional group from the series hydrogen, acyl, alkyl, aryl or represents a bifunctional group which is linked to the radical Z;
E represents an electron-withdrawing radical;
X represents the radicals xe2x80x94CHxe2x95x90 or xe2x95x90Nxe2x80x94, where the radical xe2x80x94CHxe2x95x90 may be linked to the radical Z instead of a H atom;
Z represents a monofunctional group from the series alkyl, xe2x80x94Oxe2x80x94R, xe2x80x94Sxe2x80x94R,
or represents a bifunctional group which is linked to the radical A. or the radical
Particular preference is given to compounds of the formula (I) in which the radicals have the following meaning:
R represents hydrogen and represents optionally substituted radicals from the series acyl, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl.
Examples of acyl radicals are formyl, alkylcarbonyl, arylcarbonyl, alkylsulphonyl, arylsulphonyl, (alkyl-)-(aryl-)-phosphoryl, which may themselves be substituted.
Examples of alkyl are C1-C10-alkyl, in particular C1-C4-alkyl, specifically methyl, ethyl, i-propyl, sec- or t-butyl, which may themselves be substituted.
Examples of aryl are phenyl, naphthyl, in particular phenyl.
Examples of aralkyl are phenylmethyl, phenethyl.
Examples of heteroaryl are heteroaryl having up to 10 ring atoms and N, O, S, in particular N, as hetero atoms. Specific examples are thiophenyl, furyl, thiazolyl, imidazolyl, pyridyl, benzothiazolyl.
Examples of heteroarylalkyl are heteroarylmethyl, heteroarylethyl having up to 6 ring atoms and N, O, S, in particular N, as hetero atoms.
Substituents which may be mentioned by way of example and by way of preference are:
xe2x80x83alkyl having preferably 1 to 4, in particular 1 or 2, carbon atoms, such as methyl, ethyl, n- and i-propyl and n-, i- and t-butyl; alkoxy having preferably 1 to 4, in particular 1 or 2, carbon atoms, such as methoxy, ethoxy, n- and i-propyloxy and n-, i- and t-butyloxy; alkylthio having preferably 1 to 4, in particular 1 or 2, carbon atoms, such as methylthio, ethylthio, n- and i-propylthio and n-, i- and t-butylthio; halogenoalkyl having preferably 1 to 4, in particular 1 or 2, carbon atoms and preferably 1 to 5, in particular 1 to 3, halogen atoms, the halogen atoms being identical or different, and preferred halogen atoms being fluorine, chlorine or bromine, in particular fluorine, such as trifluoromethyl, hydroxyl; halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine, cyano; nitro; amino; monoalkyl- and dialkylamino having preferably 1 to 4, in particular 1 or 2, carbon atoms per alkyl group, such as methylamino, methylethylamino, n- and i-propylamino and methyl-n-butylamino; carboxyl, carbalkoxy having preferably 2 to 4, in particular 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy; sulpho (xe2x80x94SO3H); alkylsulphonyl having preferably 1 to 4, in particular 1 or 2, carbon atoms, such as methylsulphonyl and ethylsulphonyl; arylsulphonyl having preferably 6 or 10 aryl carbon atoms, such as phenylsulphonyl, and also heteroarylamino and heteroarylalkylamino such as chloropyridylamino and chloropyridylmethylamino.
A represents hydrogen and optionally substituted radicals from the series acyl, alkyl, aryl, which are preferably as defined above, A furthermore represents a bifunctional group. Examples include optionally substituted alkylene having 1 to 4, in particular 1 or 2, C atoms, examples of substituents being the substituents which have been mentioned further above.
A and Z together with the atoms to which they are attached may form a saturated or unsaturated heterocyclic ring. The heterocyclic ring may contain a further 1 or 2 identical or different hetero atoms and/or hetero groups. Preferred hetero atoms are oxygen, sulphur or nitrogen, and preferred hetero groups are N-alkyl, where the alkyl of the N-alkyl group contains preferably 1 to 4, in particular 1 or 2, carbon atoms. Examples of alkyl include methyl, ethyl, n- and i-propyl and n-, i- and t-butyl. The heterocyclic ring contains 5 to 7, preferably 5 or 6 ring members. Examples of the heterocyclic ring include pyrrolidine, piperidine, piperazine, hexamethylenimine, morpholine and N-methylpiperazine.
E represents an electron-withdrawing radical, specific examples being NO2, CN, halogenoalkylcarbonyl such as 1,5-halogeno-C1-C4-carbonyl, in particular COCF2.
X represents xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90
Z represents optionally substituted radicals alkyl, xe2x80x94OR, xe2x80x94SR, xe2x80x94NRR, where R and the substituents are preferably as defined above.
Z, together with the atom to which it is attached and the radical
xe2x80x83instead of X, may form a saturated or unsaturated heterocyclic ring. The heterocyclic ring may contain a further 1 or 2 identical or different hetero atoms and/or hetero groups. Preferred hetero atoms are oxygen, sulphur or nitrogen and preferred hetero groups are n-alkyl, where the alkyl or N-alkyl group contains preferably 1 to 4, preferably 1 or 2, carbon atoms. Examples of alkyl include methyl, ethyl, n- and i-propyl and n-, i- and t-butyl. The heterocyclic ring contains 5 to 7, preferably 5 or 6, ring members. Examples of the heterocyclic ring include pyrrolidine, piperidine, piperazine, hexamethyleneimine, morpholine and N-methylpiperazine.
The agonists and antagonists of the nicotinic acetylcholine receptors are preferably compounds of the formula (I)
R represents
where
n represents 1 or 2,
Subst. represents one of the abovementioned substituents, especially halogen, in particular chlorine, and A, Z, X and E are each as defined above.
Specific examples are the following compounds:
Very particularly preferred agonists and antagonists of the nicotinic acetylcholine receptors are compounds of the formulae below:
in particular the compound of the formula
The active compound combination of fipronil and agonists and antagonists of nicotinic acetylcholine receptors of the formula (I) are very useful for protecting industrial materials, in particular wood, against attack by wood-destroying insects, such as, for example,
1. Beetles
Hylotrupes bajulus, Chlorophorus pilosis, Anabium punctatum, Xestobium rufovillosum, Ptilinus pecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthes rugicollis, Xyleborus spec. Tryptodendron spec. Apate monachus, Bostrychus capucins, Heterobostrychus bruneus, Sinoxylon spec. Dinoderus minutus
2. Dermapterans
Sirex juvencus, Urocerus gigas, Urocerus gigas taignus, Urocerus augur
3. Termites
Kalotermes flavicollis, Cryptotermes brevis, Heterotermes indicola, Reticulitermes flavipes, Reticulitermes santonensis, Reticulitermes lucilugus, Mastotermes darwiniensis, Zootermopsis nevadensis, Coptotermes formosanus.
The ratio of the compounds of the formulae (I) employed and fipronil, and the total amount of the mixture, depends on the species and the occurrence of the insects. The optimum ratios and total application rates can be determined upon each use in each case by test series. In general, the ratio of the compounds of the general formulae (I) and fipronil is 1:100 to 100:1, preferably 1:10 to 10:1.
In general, the active compound combinations according to the invention can be incorporated into all compositions or formulations for the protection of wood, for example by mixing the active compounds with solvent or diluent, emulsifier, dispersant and/or binder or fixative, water repellent, if appropriate desiccants and UV stabilizers and, if appropriate, colorants and pigments and other processing auxiliaries, or as an additive to any other formulations for the protection of wood.
The solvent and/or diluent used is an organochemical solvent or solvent mixture and/or an oily or oil-type organochemical solvent or solvent mixture of low volatility and/or a polar organochemical solvent or solvent mixture and/or water and at least one emulsifier and/or wetting agent or consists thereof.
Organochemical solvents which are preferably employed are oily or oil-type solvents having an evaporation number of above 35 and a flashpoint of above 30xc2x0 C., preferably above 45xc2x0 C. Substances which are used as such oily and oil-type solvents which have low volatility and are insoluble in water are suitable mineral oils or their aromatic fractions, or mineral-oil-containing solvent mixtures, preferably white spirit, petroleum and/or alkylbenzene.
Substances which are advantageously used are mineral oils with a boiling range of 170 to 220xc2x0 C., white spirit with a boiling range of 170 to 220xc2x0 C., spindle oil with a boiling range of 250 to 350xc2x0 C., petroleum or aromatics of boiling range 160 to 280xc2x0 C., essence of turpentine and the like.
In a preferred embodiment, liquid aliphatic hydrocarbons with a boiling range of 180 to 210xc2x0 C. or high-boiling mixtures of aromatic and aliphatic hydrocarbons with a boiling range of 180 to 220xc2x0 C. and/or spindle oil and/or monochloronaphthalene, preferably xcex1-monochloronaphthalene, are used.
The organic oily or oil-type solvents of low volatility having an evaporation number of above 35 and a flashpoint of above 30xc2x0 C., preferably above 45xc2x0 C., can be partially replaced by organochemical solvents of high or medium volatility, with the proviso that the solvent mixture also has an evaporation number of above 35 and a flashpoint of above 30xc2x0 C., preferably above 45xc2x0 C., and that the insecticide/fungicide mixture is soluble or emulsifiable in this solvent mixture.
In a preferred embodiment, part of the organochemical solvent or solvent mixture or an aliphatic polar organochemical solvent or solvent mixture is replaced. Substances which are preferably used are aliphatic organochemical solvents having hydroxyl and/or ester and/or ether groups, such as, for example, glycol ether, esters and the like.
A particularly useful solvent/diluent is water, if appropriate as a mixture with one or more of the abovementioned organochemical solvents/diluents, emulsifiers and dispersants.
The organochemical binders used within the scope of the present invention are the synthetic resins and/or binding drying oils which are known per se and can be diluted with water and/or are soluble or dispersible or emulsifiable in the organochemical solvents employed, in particular binders composed of, or comprising, an acrylate resin, a vinyl resin, for example polyvinyl acetate, polyester resin, polycondensation or polyaddition resin, polyurethane resin, alkyd resin or modified alkyd resin, phenol resin, hydrocarbon resin, such as indene/coumarone resin, silicone resin, drying vegetable and/or drying oils and/or physically drying binders based on a natural and/or synthetic resin.
The synthetic resin used as the binder can be employed in the form of an emulsion, dispersion or solution. Up to 10% by weight of bitumen or bituminous substances can also be used as binders. In addition, colorants, pigments, water repellents, odour-masking substances and inhibitors or anticorrosives known per se and the like can also be employed.
The composition or the concentrate preferably comprises, in accordance with the invention, at least one alkyd resin or modified alkyd resin and/or a drying vegetable oil as the organochemical binder. Preferably used according to the invention are alkyd resins with an oil content of over 45% by weight, preferably 50 to 68% by weight.
All or some of the abovementioned binder can be replaced by a fixative (mixture) or a plasticizer (mixture). These additives are intended to prevent volatilization of the active compounds and crystallization or precipitation. They preferably replace 0.01 to 30% of the binder (based on 100% of the binder employed).
The plasticizers are from the chemical classes of the phthalic esters, such as dibutyl phthalate, dioctyl phthalate or benzylbutyl phthalate, the phosphoric esters, such as tributyl phosphate, the adipic esters, such as di-(2-ethylhexyl) adipate, the stearates, such as butyl stearate or amyl stearate, the oleates, such as butyl oleate, the glycerol ethers or relatively high-molecular-weight glycol ethers, glycerol esters and p-toluene-sulphonic esters.
Fixatives are chemically based on polyvinyl alkyl ethers, such as, for example, polyvinyl methyl ether, or ketones, such as benzophenone or ethylene benzophenone, amines, such as, for example, alkanolamines, such as monoethanolamine or ammonia.
Wood which can be protected by the active compound mixture according to the invention or compositions comprising such a mixture are to be understood as meaning, for example: construction timber, wooden beams, railway sleepers, bridge components, jetties, wooden vehicles, boxes, pallets, containers, telephone poles, wood lagging, windows and doors made of wood, plywood, particle board, joiner""s articles, or wood products which, quite generally, are used in the construction of houses or in joinery.
Particularly effective protection of wood is achieved by large-scale industrial impregnation processes, for example vacuum, double-vacuum or pressure processes.
The insecticidal compositions or concentrates used for the protection of wood and timber products comprise the active compound combination in a concentration of 0.001 to 95% by weight, in particular 0.001 to 60% by weight.
Using the compositions according to the invention, it is possible to replace, in an advantageous manner, the insecticidal compositions which are currently available by more effective compositions. The compositions according to the invention exhibit good stability and have an advantageous broad insecticidal activity spectrum.
In ready-to-use applications, the mixtures according to the invention may also be present, if appropriate, as a mixture with other insecticides and, if appropriate, also with one or more fungicides in order to achieve additional activity against wood-destroying and wood-discoloring fungi. In many cases, additional synergisms are then observed.
Examples of insecticides which may optionally be admixed include:
phosphoric esters, such as azinphos-ethyl, azinphos-methyl, xcex1-1(4-chlorophenyl)-4-(O-ethyl, S-propyl)phosphoryloxy-pyrazole, chlorpyrifos, coumaphos, demeton, demeton-S-methyl, diazinone, dichlorovos, dimethoate, ethoate, ethoprophos, etrimfos, fenitrothion, fenthion, heptenophas, parathion, parathion-methyl, phosalone, poxim, pirimiphos-ethyl, pirimiphos-methyl, profenofos, prothiofos, sulfprofos, triazophos and trichlorphon; carbamates, such as aldicarb, bendiocarb, xcex1-2-(1-methylpropyl)-phenyl methylcarbamate, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, cloethocarb, isoprocarb, methomyl, oxamyl, pirimicarb, promecarb, propoxur and thiodicarb;
organosilicon compounds, preferably dimethyl(phenyl)silyl-methyl 3-phenoxybenzyl ethers, such as dimethyl-(4-ethoxyphenyl)-silylmethyl 3-phenoxybenzyl ether or (dimethylphenyl)-silyl-methyl 2-phenoxy-6-pyridylmethyl ethers such as, for example, dimethyl-(9-ethoxy-phenyl)-silylmethyl 2-phenoxy-6-pyridylmethyl ether or [(phenyl)-3-(3-phenoxyphenyl)-propyl[(dimethyl)-silanes such as, for example, (4-ethoxyphenyl)-[3-(4-fluoro-3-phenoxyphenyl-propyl]dimethyl-silane, silafluofen;
pyrethroids, such as allethrin, alphamethrin, bioresmethrin, byfenthrin, cycloprothrin, cyfluthrin, decamethrin, cyhalothrin, cypermethrin, deltamethrin, alpha-cyano-3-phenyl-2-methylbenzyl 2,2-dimethyl-3-(2-chloro-2-trifluoro-methylvinyl)cyclopropanecarboxylate, fenpropathrin, fenfluthrin, fenvalerate, flucythrinate, flumethrin, fluvalinate, permethrin, resmethrin and tralomethrin;
nitroimines and nitromethylenes, such as 1-[(6-chloro-3-pyridinyl)-methyl]4,5-dihydro-N-nitro-1H-imidazol-2-amine (imidacloprid), N-[(6-chloro-3-pyridyl)methyl-]N2-cyano-N1-methylacetamide (NI-25);
abamectin, AC 303, 630, acephate, acrinathrin, alanycarb, aldoxycarb, aldrin, amitraz, azamethiphos, Bacillus thuringiensis, phosmet, phosphamidon, phosphine, prallethrin, propaphos, propetamphos, prothoate, pyraclofos, pyrethrins, pyridaben, pyridafenthion, pyriproxyfen, quinalphos, RH-7988, rotenone, sodium fluoride, sodium hexafluorosilicate, sulfotep, sulfuryl fluoride, tar oils, teflubenzuron, tefluthrin, temephos, terbufos, tetrachlorvinphos, tetramethrin, O-tert-butyl-pyrimidin-5-yl-o-isopropyl-phosphorothiate, thiocyclam, thiofanox, thiometon, tralomethrin, triflumuron, trimethacarb, vamidothion, Verticillium Lacanii, XMC, xylylcarb, benfuracarb, bensultap, bifenthrin, bioallethrin, MERbioallethrin (S)-cyclopentenyl isomer, bromophos, bromophos-ethyl, buprofezin, cadusafos, calcium polysulphide, carbophenothion, cartap, quinomethionate, chlordane, chlorfenvinphos, chlorfluazuron, chlormephos, chloropicrin, chlorpyrifos, cyanophos, beta-cyfluthrin, alpha-cypermethrin, cyophenothrin, cyromazine, dazomet, DDT, demeton-S-methylsulphone, diafenthiuron, dialifos, dicrotophos, diflubenzuron, dinoseb, deoxabenzofos, diazacarb, disulfoton, DNOC, empenthrin, endosulfan, EPN, esfenvalerate, ethiofencarb, ethion, etofenprox, fenobucarb, fenoxycarb, fensulfothion, fipronil, flucycloxuron, flufenprox, flufenoxuron, fonofos, formetanate, formothion, fosmethilan, furathiocarb, heptachlor, hexaflumuron, hydramethylnon, hydrogen cyanide, hydroprene, IPSP, isazofos, isofenphos, isoprothiolane, isoxathion, iodofenphos, kadethrin, lindane, malathion, mecarbam, mephosfolan, mercurous, chloride, metam, Metarthizium, anisopliae, methacrifos, methamidophos, methidathion, methiocarb, methoprene, methoxychlor, methyl isothiocyanate, metholcarb, mevinphos, monocrotophos, naled, Neodiprion sertifer NPV, nicotine, omethoate, oxydemeton-methyl, pentachlorophenol, petroleum oils, phenothrin, phenthoate, phorate.
The other insecticides that may optionally be admixed may also be from the class of the compounds of the general formula (I).
Fungicides which may optionally be admixed are preferably:
Triazoles such as:
azaconazole, propiconazole, tebuconazole, cyproconazole, metconazole, amitrole, azocyclotin, BAS 480F, bitertanol, difenoconazole, fenbuconazole, fenchlorazole, fenethanil, fluquinconazole, flusilazole, flutriafol, imibenconazole, isozofos, myclobutanil, paclobutrazol, (xc2x1)-cis-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)-cycloheptanol, tetraconazole, triadimefon, triadimenol, triapenthenol, triflumizole, triticonazole, uniconazole and their metal salts and acid adducts.
Imidazoles such as:
imazalil, pefurazoate, prochloraz, triflumizole, 2-(1-tert-butyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol, thiazolecarboxanilides such as 2xe2x80x2,6xe2x80x2-dibromo-2-methyl-4-trifluoromethoxy-4xe2x80x2-trifluoromethyl-1,3-thiazole-5-carboxanilide, 1-imidazolyl-1-(4xe2x80x2-chlorophenoxy)-3,3-dimethylbutan-2-one and their metal salts and acid adducts.
Methyl(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]3-methoxyacrylate, methyl(E)-2-[2-[6-(2-thioamidophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[6-(2,6-difluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[3-(pyrimidin-2-yloxy)phenoxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[3-(5-methylpyrimidin-2-yloxy)-phenoxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[3-(phenyl-sulphonyloxy)phenoxy]phenyl-3-methoxyacrylate, methyl(E)-2-[2-[3-(4-nitrophenoxy)phenoxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-phenoxyphenyl]-3-methoxyacrylate, methyl(E)-2-[2-(3,5-dimethylbenzoyl)pyrrol-1-yl]-3-methoxyacrylate, methyl(E)-2-[2-(3-methoxyphenoxy)phenyl]-3-methoxyacrylate, methyl(E)-2[2-(2-phenylethen-1-yl)-phenyl]-3-methoxyacrylate, methyl(E)-2-[2-(3,5-dichlorophenoxy)pyridin-3-yl]-3-methoxyacrylate, methyl(E)-2-(2-(3-( 1,1,2,2-tetrafluoroethoxy)phenoxy)phenyl)-3-methoxyacrylate, methyl(E)-2-(2-[3-(alpha-hydroxybenzyl)phenoxy]phenyl)-3-methoxyacrylate, methyl(E)-2-(2-(4-phenoxy-pyridin-2-yloxy)phenyl)-3-methoxyacrylate, methyl(E)-2-[2-(3-n-propyloxyphenoxy)phenyl]3-methoxyacrylate, methyl(E)-2-[2-(3-isopropyloxyphenoxy)phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[3-(2-fluorophenoxy)phenoxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-(3-ethoxyphenoxy)phenyl]-3-methoxyacrylate, methyl(E)-2-[2-(4-tert-butyl-pyridin-2-yloxy)phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[3-(3-cyanophenoxy)phenoxy]phenyl]-3-methoxyacry late, methyl(E)-2-[2-[(3-methyl-pyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[6-(2-methylphenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl(E)-2-[2-(5-bromopyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate, methyl(E)-2-[2-(3-(3-iodopyridin-2-yloxy)phenoxy)phenyl]-3-methoxyacrylate, methyl(E)-2-[2-[6-(2-chloropyridin-3-yloxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, (E),(E)methyl-2-[2-(5,6-dimethylpyrazin-2-ylmethyloximinomethyl)phenyl]-3-methoxyacrylate, (E)-methyl-2-{2-[6-(6-methylpyridin-2-yloxy)pyrimidin-4-yloxy]phenyl}-3-methoxy-acrylate, (E),(E)methyl-2-{2-(3-methoxyphenyl)methyloximinomethyl]-phenyl}-3-methoxyacrylate, (E)methyl-2-{2-(6-(2-azidophenoxy)-pyrimidin-4yloxy]phenyl}-3-methoxyacrylate, (E), (E)methyl-2-{2-[6-phenylpyrimidin-4-yl)-methyloximinomethyl]phenyl}-3-methoxyacrylate, (E),(E)methyl-2-{2-[(4-chlorophenyl)-methyloximinomethyl]phenyl}-3-methoxyacrylate,(E)methyl-2-{2-[6-(2-n-propylphenoxy)-1,3,5-triazin-4-yloxy]phenyl}-3-methoxyacrylate, (E), (E)methyl-2-{2-[(3-nitrophenyl)methyloximinomethyl]phenyl}-3-methoxyacrylate;
Succinate dehydrogenase inhibitors such as:
fenfuram, furcarbanil, cyclafluramid, furmecyclox, seedvax, metsulfovax, pyrocarbolid, oxycarboxin, shirlan, mebenil (mepronil), benodanil, flutolanil (Moncut);
naphthalene derivatives such as terbinafine, naftifine, butenafine, 3-chloro-7-(2-aza-2,7,7-trimethyl-oct-3-en-5-ine);
sulfenamides such as dichlofluanid, tolylfluanid, folpet, fluorfolpet; captan, captofol; benzimidazoles such as carbendazim, benomyl, furathiocarb, fuberidazole, thiophonatmethyl, thiabendazole or their salts;
morpholine derivatives such as fenpropimorph, falimorph, dimethomorph, dodemorph, aldimorph, fenpropidine and their arylsulphonates, such as, for example, p-toluenesulphonic acid and p-dodecylphenyl-sulphonic acid;
dithiocarbamates, cufraneb, ferbam, mancopper, mancozeb, maneb, metam, metiram, thiram zeneb, ziram:
benzothiazoles, such as 2-mercaptobenzothiazole;
benzamides, such as 2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide;
boron compounds, such as boric acid, boric esters, borax;
formaldehyde and formaldehyde-releasing compounds, such as benzyl alcohol mono(poly)-hemiformal, oxazolidine, hexa-hydro-S-triazines, N-methylolchloroacetamide, paraformadehyde, nitropyrin, oxolinic acid, tecloftalam;
tris-N-(cyclohexyldiazeneiumdioxy)-aluminium, N-(cyclo-hexyldiazeniumdioxy)-tributyltin or K salts, bis-N-(cyclohexyldiazeniumdioxy)-copper, N-methylisothiazolin-3-one, 5-chloro-N-methylisothiazolin-3-one, 4,5-dichloro-N-octylisothiazolin-3-one, N-octyl-isothiazolin-3-one, 4,5-trimethylene-isothiazolinone, 4,5-benzoisothiazolinone, N-methylolchloroacetamide;
aldehydes, such as cinnamaldehyde, formaldehyde, glutaraldehyde, xcex2-bromocinnamaldehyde;
thiocyanates, such as thiocyanatomethylthiobenzothiazole, methylenebisthiocyanate, and the like;
quaternary ammonium compounds, such as benzyldimethyltetradecylammonium chloride, benzyldimethyldodecylammonium chloride, didecyldimethaylammonium chloride;
iodine derivatives, such as diiodomethyl p-tolyl sulphone, 3-iodo-2-propinyl alcohol, 4-chlorophenyl-3-iodopropargyl formal, 3-bromo-2,3-diiodo-2-propenyl ethylcarbamate, 2,3,3-triiodoallyl alcohol, 3-bromo-2,3-diiodo-2-propenyl alcohol, 3-iodo-2-propinyl n-butylcarbamate, 3-iodo-2-propinyl n-hexylcarbamate, 3-iodo-2-propinyl cyclohexyl-carbamate, 3-iodo-2-propinyl phenylcarbamate;
phenol derivatives, such as tribromophenol, tetrachlorophenol, 3-methyl-4-chlorophenol, 3,5-dimethyl-4-chlorophenol, phenoxyethanol, dichlorophene, o-phenylphenol, m-phenylphenol, p-phenylphenol, 2-benzyl-4-chlorophenol and their alkali metal and alkaline earth metal salts;
microbicides having an activated halogen group, such as chloroacetamide, bronopol, bronidox, tectamer, such as 2-bromo-2-nitro-1,3-propanediol, 2-bromo-4xe2x80x2-hydroxyacetophenone, 2,2-dibromo-3-nitrile-propionamide, 1,2-dibromo-2,4-dicyanobutane, xcex2-bromo-xcex2-nitrostyrene;
pyridines, such as 1-hydroxy-2-pyridinethione (and their Na, Fe, Mn, Zn salts), tetrachloro-4-methylsulphonylpyridine, pyrimethanol, mepanipyrim, dipyrithion, 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridine;
metal soaps, such as tin naphthenate, copper naphthenate, zinc naphthenate, tin octoate, copper octoate, zinc octoate, tin 2-ethylhexanoate, copper 2-ethylhexanoate, zinc 2-ethylhexanoate, tin oleate, copper oleate, zinc oleate, tin phosphate, copper phosphate, zinc phosphate, tin benzoate, copper benzoate and zinc benzoate;
metal salts, such as copper hydroxycarbonate, sodium dichromate, potassium dichromate, potassium chromate, copper sulphate, copper chloride, copper borate, zinc fluorosilicate, copper fluorosilicate, in particular mixtures with fixatives;
oxides, such as tributyltin oxide, Cu2O, CuO, ZnO;
dialkyldithiocarbamates, such as Na and Zn salts of dialkyldithiocarbamates, tetramethylthiuram disulphide, potassium N-methyl-dithiocarbamate;
nitriles, such as 2,4,5,6-tetrachloroisophthalodinitrile, disodium cyanodithioimidocarbamate;
quinolines, such as 8-hydroxyquinoline, and their Cu salts;
mucochloric acid, 5-hydroxy-2(5H)-furanone;
4,5-dichlorodithiazolinone,4,5-benzodithiazolinone, 4,5-trimethylenedithiazolinone,4,5-dichloro-(3H)-1,2-dithiol-3-one, 3,5-dimethyl-tetrahydro-1,3,5-thiadiazine-2-thione, N-(2-p-chlorobenzoylethyl)-hexaminium chloride, potassium N-hydroxymethyl-Nxe2x80x2-methyldithiocarbamate,
2-oxo-2-(4-hydroxy-phenyl)acetohydroximic acid chloride, phenyl-(2-chloro-cyano-vinyl)sulphone, phenyl-( 1,2-dichloro-2-cyano-vinyl)sulphone;
Ag, Zn or Cu-containing zeolites, alone or enclosed in polymeric active compounds, or else mixtures of more than one of the abovementioned fungicides.
As already mentioned, the active compound mixtures are suitable for controlling animal pests, in particular insects, arachnids and nematodes, encountered in agriculture, in forests, in the protection of stored products, and in the hygiene field, and have good plant tolerance and favourable toxicity to warm-blooded animals. They are active against normally sensitive and resistant species and against all or some stages of development. The abovementioned pests include:
From the order of the Isopoda, for example, Oniscus asellus, Armadillidium vulgare and Porcellio scaber.
From the order of the Diplopoda, for example, Blaniulus guttulatus.
From the order of the Chilopoda, for example, Geophilus carpophagus and Scutigera spec.
From the order of the Symphyla, for example, Scutigerella immaculata.
From the order of the Thysanura, for example, Lepisma saccharina.
From the order of the Collembola, for example, Onychiurus armatus.
From the order of the Orthoptera, for example, Blatta orientalis, Periplaneta americana, Leucophaea maderae, Blattella germanica, Acheta domesticus, Gryllotalpa spp., Locusta migratoria migratorioides, Melanoplus differentialis and Schistocerca gregaria.
From the order of the Dermaptera, for example, Forficula auricularia.
From the order of the Isoptera, for example, Reticulitermes spp.
From the order of the Anoplura, for example, Pediculus humanus corporis, Haematopinus spp. and Linognathus spp.
From the order of the Mallophaga, for example, Trichodectes spp. and Damalinea spp.
From the order of the Thysanoptera, for example, Hercinothrips femoralis and Thrips tabaci.
From the order of the Heteroptera, for example, Eurygaster spp., Dysdercus intermedius, Piesma quadrata, Cimex lectularius, Rhodnius prolixus and Triatoma spp.
From the order of the Homoptera, for example, Aleurodes brassicae, Bemisia tabaci, Trialeurodes vaporariorum, Aphis gossypii, Brevicoryne brassicae, Cryptomyzus ribis, Doralis fabae, Doralis pomi, Eriosoma lanigerum, Hyalopterus arundinis, Macrosiphum avenae, Myzus spp., Phorodon humuli, Rhopalosiphum padi, Phylloxera vastatrix, Pemphigus spp., Empoasca spp., Euscelis bilobatus, Nephotettix cincticeps, Lecanium corni, Saissetia oleae, Laodelphax striatellus, Nilaparvata lugens, Aonidiella aurantii, Aspidiotus hederae, Pseudococcus spp. and Psylla spp.
From the order of the Lepidoptera, for example, Pectinophora gossypiella, Bupalus piniarius, Cheimatobia brumata, Lithocolletis blancardella, Hyponomeuta padella, Plutella maculipennis, Malacosoma neustria, Euproctis chrysorrhoea, Lymantria spp. Bucculatrix thurberiella, Phyllocnistis citrella, Agrotis spp., Euxoa spp., Feltia spp., Earias insulana, Heliothis spp., Laphygma exigua, Mamestra brassicae, Panolis flammea, Prodenia litura, Spodoptera spp., Trichoplusia ni, Carpocapsa pomonella, Pieris spp., Chilo spp., Pyrausta nubilalis, Ephestia kuehniella, Galleria mellonella, Tineola bisselliella, Tinea pellionella, Hofmannophila pseudospretella, Cacoecia podana, Capua reticulana, Choristoneura fumiferana, Clysia ambiguella, Homona magnanima and Tortrix viridana.
From the order of the Coleoptera, for example, Anobium punctatum, Rhizopertha dominica, Bruchidius obtectus, Acanthoscelides obtectus, Hylotrupes bajulus, Agelastica alni, Leptinotarsa decemlineata, Phaedon cochleariae, Diabrotica spp., Psylliodes chrysocephala, Epilachna varivestis, Atomaria spp., Oryzaephilus surinamensis, Anthonomus spp., Sitophilus spp., Otiorrhynchus sulcatus, Cosmopolites sordidus, Ceuthorrhynchus assimilis, Hypera postica, Dermestes spp., Trogoderma spp., Anthrenus spp., Attagenus spp., Lyctus spp., Meligethes aeneus, Ptinus spp., Niptus hololeucus, Gibbium psylloides, Tribolium spp., Tenebrio molitor, Agriotes spp., Conoderus spp., Melolontha melolontha, Amphimallon solstitialis and Costelytra zealandica.
From the order of the Hymenoptera, for example, Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis and Vespa spp.
From the order of the Diptera, for example, Aedes spp., Anopheles spp., Culex spp., Drosophila melanogaster, Musca spp., Fannia spp., Calliphora erythrocephala, Lucilia spp., Chrysomyia spp., Cuterebra spp., Gastrophilus spp., Hyppobosca spp., Stomoxys spp., Oestrus spp., Hypoderma spp., Tabanus spp., Tannia spp., Bibio hortulanus, Oscinella frit, Phorbia spp., Pegomyia hyoscyami, Ceratitis capitata, Dacus oleae and Tipula paludosa.
From the order of the Siphonaptera, for example, Xenopsylla cheopis and Ceratophyllus spp.
From the order of the Arachnida, for example, Scorpio maurus and Latrodectus mactans.
From the order of the Acarina, for example, Acarus siro, Argas spp., Ornithodoros spp., Dermanyssus gallinae, Eriophyes ribis, Phyllocoptruta oleivora, Boophilus spp., Rhipicephalus spp., Amblyomma spp., Hyalomma spp., Ixodes spp., Psoroptes spp., Chorioptes spp., Sarcoptes spp., Tarsonemus spp., Bryobia praetiosa, Panonychus spp., Tetranychus spp.
The plant-parasitic nematodes include Pratylenchus spp., Radopholus similis, Ditylenchus dipsaci, Tylenchulus semipenetrans, Heterodera spp., Meloidogyne spp., Aphelenchoides spp., Longidorus spp., Xiphinema spp. and Trichodorus spp.
The active compound mixtures according to the invention can be present in their commercially available formulations and in use forms prepared from these formulations, as a mixture with other active compounds, such as insecticides, attractants, sterilizing agents, acaricides, nematicides, fungicides, growth-regulating substances or herbicides. The insecticides include, for example, phosphates, carbamates, carboxylates, chlorinated hydrocarbons, phenylureas and substances produced by microorganisms, inter alia. Specific examples of mixing partners include the insecticides and fungicides mentioned further above.


Controlled release powder insufflation formulations are disclosed. The powder formulation includes cohesive composites of particles containing a medicament and a controlled release carrier which preferably includes one or more polysaccharide gums of natural origin.

The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time and increasing patient compliance by reducing the number of administrations necessary to achieve the same. These advantages have been attained by a wide variety of methods.
Many controlled release delivery systems have already been developed for absorption in the gastrointestinal tract and are commercially available. Likewise, controlled release transdermal formulations are well known in the art.
Another commonly utilized path for drug delivery is via oral inhalation therapy.
Inhalations are drugs or solutions or suspensions of one or more drugs capable of administration by the nasal or oral respiratory route for local or systemic effect. There are several different delivery devices which may be used to administer drugs to a patient via the inhalation route.
Nebulizers are suitable to administer inhalation solutions or suspensions only if they produce droplets sufficiently fine and uniform in size so that the mist reaches the bronchioles. Nebulized solutions may be breathed directly from the nebulizer or from a plastic face mask, tent, or intermittent positive breathing machine. Disadvantages of nebulized systems include xe2x80x9cthrough-usexe2x80x9d dose variability and drug stability problems.
Another group of products are known as inhalations or insufflations. The British Pharmacepoeia defines an inhalation as a liquid drug delivery system whereas an insufflation is a powder delivery system for the respiratory tract. One such inhalation device is the pressurized metered dose inhaler (PMDI). Devices of this type are intended for delivering metered doses of a drug to the respiratory tract and include suspensions or solutions in a liquefied gas propellent, along with materials such as co-solvents (e.g., alcohol) and surfactants (e.g. lecithin). A metered dose inhaler contains multiple doses, often in the range of one to two hundred doses. The dose delivered is generally in the rage of 25 to 100 microliters (xcexcl) per actuation.
Powdered drugs may be administered by mechanical devices that require externally-produced pressure or, more usually, deep inhalation by the patient. The powdered drug is often contained in a capsule which is placed in a suitable device and pierced to allow the powder to exit to the outside environment when an appropriate pressure drop is created. In certain devices, the pressured drop is created by having a patient place the device in his or her mouth and inhaling. Inhalation produces conditions which act to draw the drug out of the capsule and into the respiratory tract of the patient. The device may also contain turbulence-increasing structures which aim to enhance de-agglomeration, thereby preventing larger powder particles from entering the respiratory tract.
Increasing attention is now being given in the art to dry powder inhalers.
For example, International Patent Application WO 94/04133 describes a powder composition for inhalation which contains a microfine drug such as a salbutamol sulfate and a carrier containing an anti-static agent. The carrier is calcium carbonate or a sugar, especially lactose. The amount of carrier is 95-99.99 weight percent. The compositions were said to be useful for delivery of the active agent to the lungs while providing reduced side effects such as nausea by maximizing its proportion of drug reaching the lungs.
U.S. Pat. No. 4,590,206 describes capsules, cartridges or aerosol containers containing spray-dried sodium cromoglycate in finely divided and un-agglomerated form. A substantial proportion of the individual drug particles have shapes which allow deep penetration into the lung and yet are free-flowing so as to allow capsule filling.
International Patent Application WO 93/25198 is directed to an ultrafine powder for inhalation. The powder comprises a drug and hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. More than 80 weight percent of the particles in the powder are said to have a particle diameter of 0.5-10 microns. The powder is said to be able to reach the lower windpipe and bronchi and is further said to have good deposit (storage) properties, and is further said to be capable of releasing a drug continuously.
Previously, a hetero-disperse polysaccharide excipient system and controlled release oral solid dosage forms were described in our U.S. Pat. Nos. 4,994,276, 5,128,143, and 5,135,757, all of which are hereby incorporated by reference. These systems are commercially available under the tradename TIMERx(trademark) from TIMERx Technologies, Patterson, N.Y. and Edward Mendell Co., Inc., N.Y., which is the assignee of the present invention.
It would be considered most advantageous in the art to provide new dry powder inhalation formulations which are capable of providing a slow, continuous release of drug while also being biodegradable or expellable from the pulmonary or nasal tract, and in which the active ingredient would be relatively bioavailable.
It is an object of the present invention to provide new oral or nasal inhalation carriers for a wide variety of medicaments which provide a reproducible in-vivo effect when a desired unit dose of the carrier in combination with a medicament is administered to a human patient via an oral or nasal inhalation device.
It is a further object of the present invention to provide a dry powder for oral or nasal inhalation or insufflation which comprises a cohesive composite of carrier and medicament, which provides a controlled release of medicament from the carrier in-vivo.
It is a further object of the present invention to provide a controlled release formulation for oral or nasal inhalation which is enzymatically degradable or expellable when administered in-vivo.
It is a further object of the present invention to provide a controlled release formulation for oral inhalation which enables controlled drug delivery in the naso-pharyngeal, tracheo-bronchial and combined naso-pharyngeal-bronchial regions of the pulmonary tract.
It is a further object of the present invention to provide a dry powder for inhalation therapy which is bioadhesive and which provides a controlled release of medicament when administered in-vivo.
It is a further object of the invention to provide an oral inhalation formulation for controlled release of a medicament in the upper airways of the respiratory tract.
The above-mentioned objects and others are achieved by virtue of the present invention, which relates in part to controlled release particles of a cohesive composite of a medicament together with a pharmaceutically acceptable carrier. The cohesive composite particles comprising the dry powder formulations of the invention are non-segregating. The average particle size is from about 0.1 to about 10 microns in diameter for lung delivery. For nasal delivery, the average particle size is from about 10 to about 355 microns and preferably 10-125 microns.
The pharmaceutically acceptable carrier can comprise, for example, xanthan gum, locust bean gum, galactose, other saccharides, oigosaccharides and/or polysaccharides, starch, starch fragments, dextrins, British gum and mixtures thereof. Preferably, the pharmaceutically acceptable carrier is of natural origin.
The pharmaceutically acceptable carrier can further comprise an inert saccharide diluent selected from a monosaccharide or disaccharide.
The present invention is further related to a capsule, cartridge or aerosol container containing a cohesive composite of a medicament together with a pharmaceutically acceptable polysaccharide carrier of natural origin, wherein the average particle size is from about 0.1 to about 10 microns in diameter for lung delivery. For nasal delivery, the average particle size is from about 1 to about 355 microns, and preferably from about 10 to about 125 microns.
The present invention is further directed to a method for preparing a controlled release pharmaceutical formulation for inhalation or insufflation therapy, comprising granulating a mixture of a medicament together with a polysaccharide gum of natural origin, drying the resultant granulation, and thereafter milling the resultant cohesive composite of medicament and gum to obtain particles having a diameter from about 2 to about 10 microns. In an alternative embodiment, the polysaccharide gum is first milled and then granulated with the medicament, and the mixture is then dried to obtain a granulate, and the granulate is then screened to provide a dry powder product having a particle size from about 2 to about 10 microns in diameter.
In yet another embodiment, all of the saccharide component of the pharmaceutically acceptable carrier is dissolved or dispersed in a suitable medium. The medium selected should be capable of both suspending or dissolving the saccharide component as well as dissolving the actual ingredient. The active is added to the saccharide solution or dispersion and is dissolved or dispersed therein. The solvent is then removed, e.g., by evaporation, which may include spray drying, to produce a (poly)saccharide-active composite. The composite is then milled or screened, if necessary, to produce particles in the desired diameter.
The present invention is further directed to a method of treating a patient via oral or nasal inhalation therapy, comprising preparing the cohesive composite described above, incorporated the same into a suitable inhalation device, and administering to a metered unit dose of the cohesive composite to a patient to provide a therapeutically effective dose of medicament for absorption in the upper respiratory tract or intra-nasally. The method preferably further comprises comminuting the controlled release carrier, or a granulate of controlled release carrier together with a medicament, such that the average particle size is from about 0.1 micron to about 10 microns in diameter. For purposes of the present invention, inhalation therapy shall be understood to include delivery of a medicament via oral-pharynx or nasal-pharynx routes.
In certain preferred embodiments of the invention, the controlled release carrier (comprising the gum of natural origin together with any pharmaceutically acceptable inert diluent) is included in an amount from about 99.9% to about 10%, and more preferably from about 99% to about 50%, by weight of the final product. The drug to gum ratio may be, e.g., from about 0.5:100 to about 1:1. More preferably, the drug to gum ratio is from about 1:100 to about 1:2. In embodiments of the invention where the controlled release carrier comprises both a gum of natural original and a pharmaceutically acceptable inert diluent, the total amount of controlled release carrier is form about 10 to about 90% and the pharmaceutically acceptable inert diluent is from about 89 to about 9% of the formulation, the remainder comprising the medicament(s) to be administered.
For purposes of the present invention, the term xe2x80x9ccompositexe2x80x9d shall be understood to encompass more than one particle of different chemicals, more than one particle of the same chemical or a single particle of more than one chemical. The term xe2x80x9cchemicalxe2x80x9d shall be understood the include the active ingredient or medicament, carrier and inert diluent.
By xe2x80x9ccontrolled releasexe2x80x9d it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a dosage form which provides effective levels of the medicament in-vivo for a time period of from about 1 to about 24 hours or more.
The term xe2x80x9cenvironmental fluidxe2x80x9d is meant for purposes of the present invention to encompass, e.g., an aqueous solution, such as that used for in-vitro dissolution testing, or mucous found in the pulmonary or nasal tracts.
In general, it has been recognized in the art that dry powder inhalation or insufflation formulations must consist of particles of a size of about 2 microns in diameter in order for the particles, when inhaled, to reach the alveoli of the lungs. Particles larger than 10 microns in diameter are not able to reach the deep lung when inhaled because they are collected on the back of the throat and upper airways in humans, whereas those less than 0.5 microns tend to be re-breathed or exhaled). It is a surprising discovery of this invention, therefore, that when particles are formulated which exhibit bioadhesive release characteristics like those of the present invention, particles in the range of about 0.1 micron do not tend to be exhaled and are suitable for use in inhalation therapy.
In order to prepare particles having a size of 2 microns which are useful in an inhalation formulation it is considered necessary to utilize a carrier material because particles of that small size tend to be cohesive, and further, the dose of pure drug is too small to allow for accurate dosimetry for most drugs delivered by inhalation, thereby increasing the apparent size of the groups of particles which have adhered to each other when inhaled. The separation of drug and carrier in the airway during the use of an oral inhalation device is generally due to different physical characteristics of the differently sized particles, frequently characterized by Stokes Number.
It has been found that the dry powder inhalation devices utilized in the prior art are not able to efficiently provide a dose of drug to the alveoli because they do not create enough turbulence. A high turbulence is needed to create shear conditions sufficient to isolate discrete drug particles of a size in the respirable fraction. Generally, one can expect that only 10-15% of the drug payload will be delivered into the deep lung areas for conventional devices, although this can be increased to 40-50% or more in newer devices. Further, due in part to the low efficiency of the delivery of drug to the deep lung areas, and partly due to prior art dry powder formulations themselves, many dry powder inhalation devices are considered to provide too variable a dose of medicament to be considered useful for many such medicaments.
In view of the above-mentioned problems and others, it is a goal of the present invention to provide a dose of drug which is absorbable in a controlled and efficient manner in the upper airways of the respiratory tract as well as in the deep lung areas of the respiratory tract. In these areas, generally referred to in the art as the tracheo-bronchial region, particles having a diameter of 0.1-10 microns will be able to be delivered to these areas. The amount of capillaries in the upper airways region of the respiratory tract is significantly less compared to the deep pulmonary region of the lungs, and therefore this region of the respiratory tract has not previously been targeted for drug delivery. In the present invention, the relatively fewer number of capillaries in the region is advantageously utilized to provide a slow, controlled release of drug from the cohesive composites of the dry powder formulations of the invention so as to get a longer controlled release and absorption of the medicament in comparison with the controlled release from an equivalent formulation penetrating the deep lung.
The invention relates in part to a dry powder inhalation/insufflation formulation which comprises a cohesive composite of a medicament together with a non-segregating carrier. In the aspects of the invention where the dry powder inhalation formulations of the invention are intended for lung delivery, at least 80% of the discrete polysaccharide/drug particles have an average particle size of from about 0.1 to about 10 microns. In other aspects where the drug/polysaccharide fine particles are carried on coarse saccharide particles, the composite particles will have an average particle size of from about 45 to about 355 microns, and preferably from about 63 to about 125 microns. In this manner, the cohesive composite particles, when inhaled via any dry powder inhalation device known in the art, will either be collected and absorbed mainly in the tracheo-bronchial region of the respiratory tract for 2-10 micron particles and in the deep lung for  less than 2 micron particles. The carrier which is utilized to prepare the cohesive composite particles is one which will provide a controlled release of medicament when the particles are exposed to an environmental fluid, e.g., a dissolution liquid, mobile phase or water in an in-vitro dissolution apparatus, or, in the fluids present in the respiratory tract, and in particular, in the tracheo-bronchial regions in-vivo.
The carrier material utilized in the formulations of the present invention is preferably a naturally occurring gum. Such naturally occurring gums typically include the heteropolysaccharides and homopolysaccharides. The carrier, of course, can also include mixtures of homo- and heteropolysaccharides.
The term xe2x80x9cheteropolysaccharidexe2x80x9d as used in the present invention is defined as a water-soluble polysaccharide containing two or more kinds of sugar sub-units, the heteropolysaccharide having a branched or helical configuration, and having excellent water-wicking properties and immense thickening properties.
An especially preferred heteropolysaccharide is xanthan gum, which is a high molecular weight (approximately 1,000 kDa) heteropolysaccharide. Other preferred heteropolysaccharides include derivatives of xanthan gum, such as deacylated xanthan gum, the carboxymethyl ether, the propylene glycol ester and the polyethylene glycol esters.
The homopolysaccharides useful in the present invention include galactomannan gums, which are polysaccharides composed solely of mannose and galactose. Preferred galactomannan gums are those which are capable of cross-linking with the heteropolysaccharide. Galactomannans which have higher proportions of unsubstituted mannose regions have been found to achieve more interaction with the heteropolysaccharide when exposed to an environmental fluid. Locust bean gum, which has a higher ratio of mannose to the galactose, is especially preferred as compared to other galactomannans such as guar and hydroxypropyl guar.
Other naturally occurring polysaccharide gums known to those skilled in the food and pharmaceutical arts are also useful as the controlled release carrier of the invention. Such polysaccharides include alginic acid derivatives, carageenans, tragacanth, acacia, karaya, the polyethylene glycol esters of these gums, chitin, chitosan, mucopolysaccharides, konjac, starch, substituted starches, starch fragments, dextrins, British gums having a molecular weight of about 10,000 daltons, dextrans and the like. The starches can be in either native form, i.e., ungelled starches such as potato, corn, rice, banana, etc., or gelled starches or semi-synthetic starches.
Starch and starch fragments are especially preferred polysaccharides and the combination of xanthan gum with locust bean gum is an especially preferred gum combination. In our previous patents, we described and claimed the synergistic combination of heteropolysaccharide/homopolysaccharide gums for incorporation into solid oral dosage forms. Thus, in certain embodiments, the controlled release properties of the dry powder inhalation formulation are optimized when the ratio of heteropolysaccharide gum to galactomannan gum is from about 3:1 to about 1:3, and most preferably about 1:1. However, in this embodiment, the controlled release carrier of the invention may comprise from about 1% to about 99% by weight heteropolysaccharide gum and from about 99% to about 1% by weight homopolysaccharide gum.
If desired, a cationic cross-linking agent may be included in the dry powder formulations of the present invention. The cationic cross-linking agent may comprise, e.g., monovalent or multivalent metal cations. The preferred salts are the inorganic salts, including various alkali metal and/or alkaline earth metal sulfates, chlorides, borates, bromides, citrates, acetates, lactates, etc., providing the salts are soluble. Specific examples of suitable cationic cross-linking agents include calcium chloride, sodium chloride, potassium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, and sodium fluoride. Multivalent metal cations may also be utilized. However, the preferred cationic cross-linking agents are monovalent or bivalent. Particularly preferred salts are potassium chloride and sodium chloride. The cationic cross-linking agent is included in the controlled release inhalation formulations of the present invention in an amount from about 0.1 to about 50% by weight, and more preferably from about 1% to about 10% by weight of the polysaccharide component.
In certain formulations of the invention, it may be desirable to add a pharmaceutically acceptable surfactant in a sufficient amount to either modify the release-controlling characteristics of the composite excipient/drug particles or the wetting and solubility characteristics of the drug. In such embodiments, the surfactant comprises from about 0.01 to about 10 percent of the controlled release carrier, by weight, and more preferably from about 0.1 to about 2 percent of the controlled release carrier, by weight. The surfactants which may be used in the present invention generally include pharmaceutically acceptable anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphiphilic) surfactants, and non-ionic surfactants. Suitable pharmaceutically acceptable anionic surfactants include, for example, monovalent alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid-polypeptide condensates, sulfuric acid esters, and alkyl sulfates.
Suitable pharmaceutically acceptable non-ionic surfactant such as, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylate alcohols, ethoxylated/propoxylated block polymers, and propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, SPAN""s (e.g., sorbitan esters), TWEEN""s sucrose esters, and glucose (dextrose) esters. The surfactant should be non-sternutatory so as not to irritate the mucous membranes.
Other suitable pharmaceutically acceptable surfactants/co-solvents (solubilizing) agents include acacia, benzalkonium chloride, cholesterol, emulsifying wax, docusate sodium, glyceryl monostearate, lanolin alcohols, lecithin, poloxamer, poloxytheylene castor oil derivatives, poloxyethylene sorbitan fatty acid esters, poloxyethylene stearates, sodium lauryl sulfates, sorbitan esters, stearic acid, and triethanolamine.
Mixed surfactant/wetting agent systems are also useful in conjunction with the present invention. Examples of such mixed systems include, for example, sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid.
The inert filler of the sustained release excipient preferably comprises a pharmaceutically acceptable saccharide, including a monosaccharide and/or a disaccharide. Examples of suitable inert pharmaceutical fillers include sugars such as sucrose, dextrose, lactose, galactose, fructose, mixtures thereof and the like as well as sugar alcohols such as mannitol, sorbitol, xylitol, lactitol, maltitol, galactitol and the like. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, galactose, sucrose, or mixtures thereof be used. In addition, it is to be understood that the above-mentioned sugars and sugar alcohols can also be used as carriers as well, in place of or in addition to the materials described above.
The properties and characteristics of a specific controlled release carrier or excipient system prepared according to the present invention is dependent in part on the individual characteristics of the homo- and hetero-polysaccharide constituents, in terms of polymer solubility, glass transition temperatures etc. In certain embodiments which include both a hetero- and homo-polysaccharide component with or without optional polysaccharide filler (e.g., lactose), the properties and characteristics of the resultant dry powder formulation will also be dependent in part on the synergism both between different homo- and heteropolysaccharides and between the homo- and heteropolysaccharides (severally or together) and the inert saccharide constituent(s) in modifying dissolution fluid-excipient interactions.
The dry powder insufflation/inhalation formulations are preferably prepared via a wet granulation method to obtain composite particles of medicament and carrier in the desired respirable size range (depending on whether designed for naso-pharyngeal depositions, shallow lung or deep lung deposition, or some combination thereof). In certain embodiments, such composites are provided via the use of one or more wet granulation steps. However, the dry powder formulations of the invention may be prepared according to any technique to yield an acceptable product.
On one aspect of the invention, the dry powder insufflation formulations are prepared as follows:
a drug is dissolved in a suitable solvent (e.g., water, alcohol, mixed solvents, etc.) and added to a polysaccharide or polysaccharide mixture in the desired size range. For oral insufflations, this will be 80% les than 10 microns; for nasal insufflations, the desired size range will be about 10 to about 355 microns. Where required, the polysaccharides can be sieved to obtain the required size. In case where the polysaccharide requires size reduction, a suitable milling method may be used, such as fluid energy milling (e.g., with micronizers or jet mills); hammer milling, vibrational milling, ball milling, etc. In some cases, it will be more beneficial to carry out the milling procedure below the glass transition temperature or for other reasons, to use cryogenic milling (using liquid CO2, N2, or other suitable cooling aid).
The concentration (or volume) of drug solution added to such fine polysaccharide particles will be an amount sufficient to provide enough wetting contact to create sufficient drug absorption into the polysaccharide surface and absorption onto the surface (this is especially important for starch) so as to yield the controlled release characteristics required. This will typically require an aqueous concentration of 10-50% w/w of polysaccharides. The absolute concentration being dependent on other method factors including time of wetted contact of solution with polysaccharide surfaces and/or temperatures during or preceding wetted contact. This latter parameter is particularly important in the case of polysaccharides which require elevated temperatures to undergo solubility/gel transformations in certain circumstances (e.g., start to starch mucilage or locust bean gum sol to gel transformation). The contact time is preferably in the range of about 1 to 30 minutes in a high speed mixer, processor or other granulating means. The elevated temperature will be 80xc2x0 to 100xc2x0 C. for starch and locust bean gum, although this is preferably not the temperature following contact with drug solution.
The contacted drug-polysaccharide wet mass can then be granulated in the usual way using either a high speed mixture granulator or spray granulated to provide liquid contact or other suitable method to provide composite particles in the entrainable size range (for delivery from an insufflator) usually 45-355 microns (and preferably 63-95 microns for non-compression insufflation). The powder or granular material is then dried, for example, using a tray drier or fluidized bed drier operated at approximately 60xc2x0 C. for a sufficient time to produce equilibrium moisture content conditions in the powder/granules. In the case of some drugs/bioactives using a freeze drying method so as to avoid physical/chemical degradation. Finally, for some presentations (inhaler types or clinical uses), it may be desirable to apply a final further size reduction to the dried powder/granules. This can be carried out using one of the methods described above or by sieving.
In another aspect of the invention, a second method for preparing the insufflation formulations of the present invention is provided. The method described above is followed except that the volume of liquid used is much higher (e.g., 50-99% w/w water to polysaccharides) so as to provide a more complete gelation/solubilization of the polysaccharide components before or during contact with the drug solution. In such cases, the drying method may be by one of the methods described in the procedure described above or by spray drying or drum drying or spin flash drying, moving film drying or other suitable method. Alternatively, a de-watering step can be introduced prior to drying, e.g., using osmotic effects across a semi-permeable membrane. If necessary, final dried drug-loaded gel matrix can then be milled to provide powder in the desired size range using one of the methods described above.
A still further aspect of the invention provides a third method for preparing the formulations of the present invention. The first method is repeated except that the drug is milled or spray dried to the respirable range (0.1 to 10 microns for pulmonary use, or higher for nasal use) and applied as a suspension to the polysaccharide system in a largely solid-semi-solid state (first method) or semi-solid/liquid state (second method). The drug suspension can either be sprayed onto the polysaccharide powder (spray granulation) or be added in a high speed mixer granulator or other granulating means.
A fourth method for preparing the formulations of the present invention includes preparing a simple dry blend of fine drug particles (0.1-10 microns) with fine polysaccharide particles (0.1-10 microns) using a suitable dry blender (e.g., Turbula(trademark) mixer).
A fifth method for preparing the formulations of the present invention includes following the fourth procedure but adding water or other suitable solvent(s) to provide a composite of the blended drug/polysaccharides. Drying and screening size reduction, if required, can be carried out as described above.
Yet another (sixth) method for preparing the formulations of the present invention includes incorporating a saccharide component with the drug and polysaccharide blend. This method includes dissolving all the saccharide component along with the drug and adding it in a manner described any of the first three methods. Alternatively, the saccharide component may be added in solution sin the solvent system as described in the fifth method. The saccharide component can also be milled to the respirable fraction (0.1-10 microns for pulmonary, 10-355 microns for nasal) and dry blended with the products prepared by any of the five foregoing methods. Alternatively, the saccharide component may be fractionated to a size range suitable for functioning as a carrier capable of enhancing powder entrainment and deaggolomeration during inspiration from a dry powder insufflator. For this purpose, the saccharide component should be in the size range 45-355 microns and preferably 63-125 microns. The composite controlled release material prepared in any of the foregoing five methods is dry blended for 5-30 minutes with the saccharide using a tumbling blender (e.g., Turbula mixer).
A seventh method of preparing the formulations of the present invention involves cases where it may be desirable to add a further inert component, such as a surfactant, lubricant, etc. This may be done by suitable addition into any of the foregoing methods. In the first, second, third and fifth methods, the addition is made in the liquid state. In the fourth and sixth methods, the additive is in the solid state and added by simple dry blending.
A wide variety of medicaments can be utilized in the dry powder inhalation/insufflation formulations of the present invention. In general, medicaments which may be used in conjunction with the invention are preferably locally acting on the pulmonary tissue and/or be absorbable from the respiratory tract in sufficient quantities to provide a therapeutically desired effect.
Such medicaments include the following:
(a) anticholinergic agents such as anisotropine, atropine, belladonna alkaloids, benztropine, biperiden, dicyclomine, glycopyrrolate, hyoscyamine, ipratropium, isopropamide, mepenzolate, methscopolamine, oxyphencyclimine, procyclidine, propantheline, scopolamine, tridihexethyl, trihexyphenidyl and cyclopentolate;
(b) corticosteroids such as beclomethasone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, clocortolone, flumethasoen, fluocinolone, fluorometholone, flurandrenolide, triamcinolone, budesonide, desoximetasone, halcinonide, amcinonide, clobetasol, diflorasone and fluocinonide, fluticasone;
(c) sympathomimetics such as albuterol, albuterol sulfate, dobutamine hydrochloride, dopamine hydrochloride, ephedrine sulfate, epinephrine, fenfluramine hydrochloride, isoetharine, isoproterenol, mephentermine sulfate, metaproterenol sulfate, metaraminol bitartrate, methoxamine hydrochloride, norepinephrine bitartrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, ritofrine hydrochloride, terbutaline sulfate, tetrahydrozoline hydrochloride, triprolidine and pseudoephedrine, and xylometazoline hydrochloride;
(d) posterior pituitary hormones such as nafarelin acetate and vasopressin;
(e) anti-hyperglycemic agents such as acetohexamide, chlorpropamide, glipizide, glyburide, insulin preparations, tolazamide and tolbutamide;
(f) decongestants such as pseudoephedrine, phenyl-propanolamine hydrochloride;
(g) bronchodilators such as albuterol, albuterol sulfate, atropine sulfate, bitolterol mesylate, dyphylline, epinephrine, ethylnorepinephrine hydrochlorde, ipratropium bromide, isoetharine, isoproterenol, metaproterenol sulfate, oxtriphylline, pirbuterol acetate, terbutaline sulfate and theophylline/aminophylline, salmeterol (and salts);
(h) beta2-adrenergic agonists such as albuterol, bitolterol mesylate, metaproterenol sulfate, pirbuterol acetate, ritodrine hydrochloride and terbutaline sulfate;
(i) antihistamines such as astemizole, azatadine maleate, brompheniramine maleate, buclizine hydrochloride, carbinoxamine, pseudoephedrine, chlorpheniramine maleate, clemastine fumarate, cyclizine, cyproheptadien hydrochloride, dexchlorpheniramine maleate, dimenhydrinate, diphenhydramine hydrochloride, hydroxyzine, meclizine hydrochloride, methdilazine hydrochloride, premethazine hydrochloride, propiomazine hydrochloride, terfenadine, trimeprazine tartrate, tripelennamine, triprolidine, cromones such as cromolyn sodium, and nedocromil (and salts).
(j) cytokines, cytokine inhibitors (e.g., leucovorin), polypeptides, peptides, polypeptides, proteins, e.g., heparin, enzymes, genes, gene fragments, hormones, and N-acetylcysteine.
The above list of drug classes and particular medicaments is by way of example only and is not meant to be exclusive.
Insufflation Inhalation Devices
In general, insufflation inhalation devices suitable for use in connection with the inventive controlled release particulate dosage forms comprise a housing having a passageway for the flow of air, in which one end of the passageway is designed for insertion in the mouth or nose, a chamber containing controlled release particles of a cohesive composite of a medicament together with a pharmaceutically acceptable polysaccharide carrier suitable for oral inhalation, where the average discrete particle size is from about 0.1 to about 10 microns in diameter for the or-pulmonary route or 10 to 355 microns for the nasal route, actuating means for releasing a unit dose of the particles into said passageway, such that the unit dose is drawn through said passageway during an inspiration by the patient and is delivered to the naso-pharynx and/or the pulmonary tract of the patient.
The formulations of the present invention may be adapted for use with respect to any oral and/or nasal insufflation device for powdered or solid medicaments. For example, the composite powder of the present invention may be compressed into a solid dosage form such as a ring tablet which is then placed into an appropriate insufflation device which includes comminuting or other means for providing discrete powder particles in the respirable fraction from the insufflation device when the device is actuated (e.g., when a unit dose of medicament is to administered via inspiration).
There are many devices described in the prior art which are useful for delivering a dose of powdered drug to the respiratory tract or naso-pharynx of a patient. Examples of such devices which would be useful in delivering the formulations of the present invention are described below.
One such device is known as the Bespak device described in PCT publication WO 92/00771, hereby incorporated by reference, and available from Innovata Biomed Limited. The device described therein includes a storage chamber for storing a powdered drug to be administered and a metering member having metering cups in which individual doses of the powdered drug are placed. Air is inhaled through an inhalation passage at one end of the device and directed into contact with the metering cup that has been filled with the powdered drug. The metering cup is oriented upwardly open to face the air stream and to enable the powder to be released from the cup. Upon inhalation, the dose is mixed with the air flow and continues through the mouthpiece to be inhaled.
The metering cups on the metering member are arranged on an outer frusto-conical wall so that each metering cup is positionable to be upwardly open and face the air flow during inhalation. The metering member rotates so that the metering cups move between a position in which the cup receives a dose of the powered drug form the storage chamber to a position in which the cup is exposed to the air flow. As one cup is exposed to the air flow, another cup is aligned with the storage chamber and is being filled with powder.
After the dose is blown from the metering cup, and upon subsequent rotation of the metering member, the cup is wiped and cleaned by a wiping element to remove any undispersed powder and then dried via a moisture absorbent material.
Another device for delivery of inhalation powders is described in U.S. Pat. No. 2,587,215 (Priestly), hereby incorporated by reference. Priestly describes an inhaler having a storage chamber containing a powdered medicament, a mixing chamber and means to move a set dose of medicament from the storage chamber to the mixing chamber. The dose is mixed with air in the mixing chamber and inhaled through a mouthpiece.
Yet another inhalation device suitable for delivering powdered inhalation drugs is described in U.S. Pat. No. 4,274,403 (Struve), hereby incorporated by reference. Struve describes an inhaler for administering a powdered drug nasally, which includes storage means for containing a quantity of the drug therein. The storage means includes a feed hole through which the powdered drug may be received from the storage means. The device further includes a dispensing head operatively coupled to the storage means for dispensing the powdered drug more nasally. The dispensing head of the Struve inhaler includes a nozzle, a body portion, a dispensing cylinder and a vent means. The nozzle is shaped to be received in the nasal passage of the user. The nozzle includes a dispensing passageway for dispensing the dose into the nasal cavity of the patient.
The body portion is located adjacent the nozzle and has a traverse bore therein. The traverse bore operatively connects the dispensing passageway in the nozzle with the feed hole leading to the drug storage means. The feed hole and the dispensing passageway are transversely offset relative to one another at the points where they enter the transverse bore.
The dispensing cylinder includes a metering chamber. The metering chamber may be selectively aligned with either the feed hole or the dispensing passageway. The dispensing cylinder is slidably received in the transverse bore for movement between a first transverse position in which the metering chamber is aligned with the feed hole and a second transverse position in which the metering chamber is aligned with the dispensing passageway. In its first position, the metering chamber can be filled with a charge of the powdered drug when the inhaler is manipulated. In the second position, places the charge of the powdered drug into the dispensing passageway for inhalation by the user.
The vent means is formed as part of the dispensing cylinder and is capable of venting the metering chamber to atmosphere only in the second position of the cylinder, i.e. when the powder disposed in the device such that it may be inhaled by the user.
Another inhaler device is disclosed in U.S. Pat. No. 4,524,769 (Wetterlin), hereby incorporated by reference. Wetterline describes a dosage inhaler for administering a micronized pharmacologically active substance to a patient. The inhaler includes a gas conduit means through which gas passes for carrying the micronized substance to be administered. The inhaler further includes a membrane having a plurality of preselected perforated portions, each portion adapted to hold and dispense a reproducible unit dose of less than 50 mg of said active substance, in dry powder form. The powder particles have particle size of less than 5 micrometers. The membrane is movably connected to the bas conduit means so that one of the preselected portions can be positioned within the gas conduit means to that the substance held in the preselected portion may be dispensed. The remaining preselected portion can be in a position external to said gas conduit means to receive said active substance. The membrane is movable through a plurality of positions whereby each preselected portion of the membrane can be successively positioned within the gas conduit to dispense the unit dose of the active substance held therein. Each preselected portion from which the active substance has been dispensed can be moved to said external position to receive active substance.
GB Patent Application No. 2,041,763, hereby incorporated by reference, describes an inhaler having a powder storage chamber and a rotatable metering member having dosing holes which open to the storage chamber in one position and open to the mixing chamber in another position. Upon rotation of the metering member, the powder is carried from the storage chamber to the mixing chamber to be inhaled.
EB 0 079 478, hereby incorporated by reference, describes an inhaler having a storage chamber, inhalation air passage and rotatable delivery member having a cavity formed therein. The delivery member is rotated from one position in which the cavity receives powder from the storage chamber to another position in which the powder falls from the cavity by the effect of gravity into a collector positioned in the air passage.
U.S. Pat. No. 4,860,740 (Kirk et al.), hereby incorporated by reference, describes an inhaler having a rotatable metering member with recesses formed therein. The recesses contain a powdered medicament. Upon rotation of the metering member, one of the recesses in exposed to the air inhalation passage to be entrained in the air stream and inhaled.
The Easyhaler(trademark), described in PCT publication WO 92/09322, hereby incorporated by reference, and available from Boehringer Ingelheim is illustrative of another suitable device for delivering the formulations of the present invention. The device includes a supply of a pulverized medical substance and a xe2x80x9cdosing meansxe2x80x9d, which is a rotatable cylinder having five uniform recesses arranged around the periphery of the cylinder. The cylinder is rotated such that one recess aligns with the supply of drug and is filled by a quantity of the drug while another recess aligns with an air channel connected to the mouthpiece. The filled recess is then rotated to another position in the direct path of an inhalation air flow. The dose is pre-set by the recessed portion of the rotatable dosing means and is flushed clean by the direct air flow through the inhalation chamber.
To operate the device, the rotating dosing means is turned so that a full dosing chamber (having already been filled up after the previous use) is rotated into alignment with the air channel leading to the mouthpiece. Upon inhalation by the user, air s drawn through apertures and nozzles directly into the dosing chamber. The air flow flushes the dosing chamber causing the drug to be carried with the air in the direction of the inhalation through the mouthpiece. The axis of the air channel is arranged at an angle to the axis of the dosing means of between 70xc2x0 and 110xc2x0, but preferably 90xc2x0 (perpendicular).
U.S. Pat. No. 5,176,132, hereby incorporated by reference, discloses a device for the administration to the lung by inhalation of a medicament in powdered form. The device includes a mouthpiece, a medicament reservoir communicating with said mouthpiece, and metering means for dispensing a dose of medicament from the reservoir. The reservoir contains a compacted body of powdered medicament including an active ingredient having a particle size of from 1 to 10 xcexcm when in loose powder form. The metering means includes a rotatable helical blade for abrading the compacted body. Thus when actuated, the helical blade abrades the compacted powdered medicament into particles capable of being inhaled into the respiratory tract of a patient.
International patent applications, PCT/EP93/01157 and PCT/EP93/01158 (assigned to GGU), hereby incorporated by reference, are directed to an inhalation device and to a annular tablet, respectively. GGU""s device includes a medicament reservoir body situated in a mouthpiece. The body forms the beginning of an inhalation tube through which the medicament is inhaled. The drug is in a compacted and annular (ring) form. In use, a face mill cutter rotates, generating particles of the drug. Upon inhalation, air flows through air inlet openings in the casing and in the area of the cutting edges of the face mill cutter. Together with depressions situated between the cutting edges, the inlet openings and the depressions form an air channel leading to the mouthpiece, through which the drug particles are inhaled.
The quantity of each dose is determined by the amount of rotations of the face mill cutter. A spring presses the inhalation tube and thus the drug body toward the face mill cutter. In operation, a wind-up button is rotated to load the spring. By pressing the trigger mechanism, the spring is released thereby rotating the upper portion to which is connected the face mill cutter.
According to PCT/EP93/01158, the supply of pharmaceutical agent is present in solid, tablet form and has an isotropic solid structure. The strength, density and composition of the solid is homogenous. The tablets are made via cold isostatic compression at pressures between 50-500 megapascals (MPa).
Compressed Formulations
The cohesive composite particles comprising the dry powder insufflation formulations of the invention are capable of being compressed into a solid mass for insertion into a suitable inhalation device. In the event that the formulation is to be compressed, an effective amount of any generally accepted pharmaceutical lubricant, such as HVO or PEG, may be added to the above-mentioned ingredients of the excipient at the time the medicament is added, or any time prior to compression into a solid dosage form. Suitable lubricants can be added in an amount of from about 0.5% to about 3% by weight of the solid dosage form. An especially preferred lubricant is sodium stearyl fumarate, NF, commercially available under the trade name Pruv(copyright) from the Edward Mendell Co., Inc.
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.

Controlled release insufflation carrier for medicaments


There is provided an apparatus for regulating the position of an adjustably positionable vehicle part such as a window or movable roof. The apparatus includes an electric drive motor having a drive shaft which is axially displaceable within a fixed limit during driving operation of the shaft. The apparatus also includes a power transfer assembly having a driven member operatively connected to the drive shaft of the electric drive motor for driving movement thereby and a damping member for damping the axial displacement of the drive shaft of the electric motor in one axial direction. The apparatus further includes a housing having a chamber compatibly dimensioned with respect to the damping member for receiving the damping member therein in a press fit disposition.

The present invention relates to an apparatus for regulating the position of an adjustably positionable vehicle part.
A regulating apparatus disclosed in German patent document G 93 13 949.7 can be used, for example, to regulate the positioning of windows, movable roofs, or seats. It is therein suggested to provide in such an apparatus damping elements on each end of the drive shaft to accommodate possible displacement within a predetermined tolerance of the drive shaft and thereby avoid the noises arising from changes in the direction of rotation of the shaft. To this end, elastomeric elements in plate form are disposed between a drive shaft housing piece and a support plate in contact with the drive shaft. The drive shaft presses the support plate against the elastomeric elements and this serves to maintain the elastomeric elements in place. However, the occurrence of a misalignment of the drive shaft or aging of the elastomeric material can prevent this arrangement from offering an optimal seating. Moreover, such events may alter the surface pressure on the elastomeric elements whereby the operating condition of the apparatus can be undesirably influenced.
The present invention provides an apparatus for regulating the position of an adjustably positionable vehicle part which advantageously enhances the reliability of the regulation of the vehicle part to its desired adjusted position. According to one aspect of the present invention, there is provided an apparatus for regulating the position of an adjustably positionable vehicle part which includes an electric drive motor having a drive shaft which is axially displaceable within a fixed limit during driving operation of the shaft. Also, the apparatus includes a power transfer assembly having a driven member operatively connected to the drive shaft of the electric drive motor for driving movement thereby and a damping member for damping the axial displacement of the drive shaft of the electric motor in one axial direction. The apparatus also includes a housing having a chamber compatibly dimensioned with respect to the damping member for receiving the damping member therein in a press fit disposition.
The apparatus of the present invention advantageously maintains the damping member in its desired position such that aging or hardening of the damping member or pressure from a misaligned drive shaft will not displace the damping member from its desired position. Also, the single step of press fitting the damping member into the chamber eliminates the need for additional pieces to maintain the damping member in the chamber.
Another advantage of the apparatus of the present invention lies in the fact that the loading of the damping member by the drive shaft can be selected independent of the already known preloading imposed on the drive shaft in the housing. The preloading of the drive shaft is directly related to its length as produced within tolerance limits, the effects of the preloading on the drive shaft due to its length can be mitigated or eliminated by proper selection of the damping member.
The chamber preferably includes an oversurface having a rib structure which includes a plurality of ribs and the damping member distributes itself around the ribs during its press fit installation, thereby ensuring a firm seating of the damping member in the chamber. Also, the ribs are distributed in spaced manner around the circumferential periphery of the chamber and this facilitates the introduction of the damping member into the chamber.
In certain circumstances, a single rib can ensure a firm seating of the damping member.
The damping member in its uncompressed condition extends axially beyond the chamber such that the drive shaft can work in an undisturbed manner with the damping member without a transfer of vibrations of the drive shaft to the housing.
If the chamber is provided with a shoulder which is engaged by a shoulder on the adjacent axial end of the drive shaft or a shoulder on a plate intermediate the damping member and the drive shaft, this arrangement sets in a straightforward way the maximum limit to which the damping member will be compressed. The damping rubber is thereby protected during the cyclic loading whereby the aging of the damping rubber is slowed and its useful life is extended.
One beneficial feature of the apparatus of the present invention is that the ribs form spaces therebetween having a collective volume capacity sufficient to accommodate the compressed damping member fully within the chamber at the maximum compression of the damping member. The spring rate of the damping member as measured with respect to its effect on the end of the drive shaft thus substantially approaches that of an unconstrained damping member. In this situation, those influences on the spring rate produced by the press fit seating of the damping member are merely negligible.
A particularly favorable spring and damping characteristic can be obtained if the length of the damping member taken in the axial direction of the drive shaft is greater than the width of the damping member measured perpendicularly to its length. In particular, a length to width ratio greater than 1.3:1 is preferred or, even more preferably, a ratio of 1.5:1. By this approach, one achieves a very flat characteristic-force per press in wayxe2x80x94so that the influence of the damping member on the shaft is virtually independent from its preload or built in tension. In this manner, a spring rate of less than 50 Newtons per millimeter can be achieved.
The use of a soft rubber and, in particular, a rubber substantially or completely formed of N-butyl beneficially enhances the spring rate.
In the event that a plate is provided intermediate the damping member and the drive shaft, it is advantageous if the plate is retained in another chamber formed in the housing which includes projections that prevent undesired movement of the plate out of the chamber.

Apparatus for regulating the position of an adjustably positionable vehicle part with drive shaft and damping member for damping its axial displacement


A power bender may be provided. The power bender may comprise a cart, a bender mechanism, and a scissor mechanism. The cart may have a zero turn radius. The bender mechanism may be configured to bend conduit. The scissor mechanism may be disposed between the cart and the bender mechanism. The scissor mechanism may be configured adjust a working height of the bender mechanism above the cart. The bender mechanism may be configured to rotate about a pivot point.

An electrical conduit is a tube used to protect and route electrical wiring in a building or non-building structure. Electrical conduit may be made of metal, plastic, fiber, or fired clay. Most conduit is rigid, but flexible conduit is used for some purposes. Conduit is generally installed by electricians at the site of installation of electrical equipment. Its use, form, and installation details are often specified by wiring regulations, such as the US National Electrical Code (NEC) and other building codes.


A device may receive a plurality of data objects from a plurality of sources; identify text data, image data, and location data of the plurality of data objects; identify relevant data objects, of the plurality of data objects, based on the text data, and/or based on the image data, based on the location data, and/or based on comparing the text data, the image data, and the location data to a predefined element that identifies values relevant to a particular group or subject area; assign scores to the relevant data objects based on the text data, the image data, and the location data; aggregate the scores, as one or more aggregated scores, with regard to one or more users associated with the relevant data objects; and/or perform one or more actions based on the one or more aggregated scores associated with the one or more users.

Social media platforms publish content that is created or curated by users of the social media platform. A publication of content may be referred to as a post. Social media posts may include textual information, audio information, video information, and/or the like. Social media posts may also be associated with metadata that can be used to determine information regarding a user that provided the content, such as location, time, user preferences, device information, and/or the like.

Scoring mechanism for discovery of extremist content